Mutations in the
RAS gene family (HRAS, KRAS, and NRAS) have been observed in a variety
of cancers (Table 1). They are activating mutations that result in continual
signal transduction, stimulating downstream signaling pathways involved in
cell growth, proliferation, invasion, and metastasis.

The KRAS
gene encodes the KRAS protein that regulates 2 such signaling pathways: PI3K/PTEN/AKT
and RAF/MEK/ERK. These pathways are targets of anti-cancer drugs that are
currently in development. Drugs targeting EGFR, which controls these pathways
upstream from KRAS, are already available. When bound to its ligand, EGFR
stimulates tyrosine kinase activity, leading to activation of KRAS and the
signaling pathways.

Current therapies
targeting EGFR are used to treat colorectal cancer (CRC) and non-small-cell
lung cancer (NSCLC) and employ either 1) monoclonal antibodies (eg, cetuximab
and panitumumab) that prevent ligand binding and EGFR activation or 2)
tyrosine kinase inhibitors (eg, erlotinib) that prevent activation of the
signaling pathways. However, if the signaling pathways are activated
independent of EGFR, as happens when the KRAS gene is mutated, these
drugs are rendered ineffective.

KRAS
mutations frequently found in neoplasms include those at exon 2 (codons 12 and
13) and exon 3 (codon 61). Mutations in KRAS codons 12 and 13 have been
associated with lack of response to EGFR-targeted therapies in both CRC and
NSCLC patients (Table 2).2-4 The National Comprehensive Cancer Network (NCCN)
recommends KRAS mutation testing before initiating EGFR-targeted
therapies for CRC or NSCLC.5 NCCN further recommends alternative therapies
be considered for patients with KRAS mutations.5

Quest Diagnostics
can perform KRAS mutation testing on formalin-fixed, paraffin-embedded
(FFPE) tumor tissue as well as bone marrow and whole blood (plasma). However,
clinical studies that have assessed the impact of KRAS mutations on
treatment response were based on testing tumor tissue only; therefore, the
preferred sample type is FFPE tumor tissue.

Table 2. Impact of
KRAS Mutations in Patients
Treated with an EGFR Antagonist2-4

Result reported: positive (homozygous or heterozygous for the mutation
detected) or negative

Interpretive Information

In patients with
advanced CRC or NSCLC, absence of a KRAS mutation predicts a greater
likelihood of response to EGFR-targeted therapies and improved survival with
such treatment. The presence of a KRAS mutation in codon 12 or 13 is
associated with a high likelihood of resistance to therapies targeting EGFR
(≥93%).6

This assay
detects mutations at codons 12, 13, and 61 of the KRAS gene;
polymorphisms or mutations at other locations that may be associated with
drug efficacy or patient outcome will not be detected. Results should be
interpreted in conjunction with other laboratory and clinical findings.